3-48584742-C-G

Position:

• chr3-48584742-C-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000094.4(COL7A1):​c.4039G>C​(p.Gly1347Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1347W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.57

Genes affected

COL7A1 (HGNC:2214): (collagen type VII alpha 1 chain) This gene encodes the alpha chain of type VII collagen. The type VII collagen fibril, composed of three identical alpha collagen chains, is restricted to the basement zone beneath stratified squamous epithelia. It functions as an anchoring fibril between the external epithelia and the underlying stroma. Mutations in this gene are associated with all forms of dystrophic epidermolysis bullosa. In the absence of mutations, however, an acquired form of this disease can result from an autoimmune response made to type VII collagen. [provided by RefSeq, Jul 2008]

COL7A1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-48584742-C-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL7A1. . Gene score misZ 1.5899 (greater than the threshold 3.09). Trascript score misZ 4.0428 (greater than threshold 3.09). GenCC has associacion of gene with recessive dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa pruriginosa, recessive dystrophic epidermolysis bullosa-generalized other, transient bullous dermolysis of the newborn, epidermolysis bullosa with congenital localized absence of skin and deformity of nails, generalized dominant dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa, nails only, acral dystrophic epidermolysis bullosa, recessive dystrophic epidermolysis bullosa inversa, pretibial dystrophic epidermolysis bullosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-48584742-C-G is Pathogenic according to our data. Variant chr3-48584742-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 17434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48584742-C-G is described in Lovd as [Pathogenic]. Variant chr3-48584742-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.4039G>C	p.Gly1347Arg	missense_variant	35/119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.4039G>C	p.Gly1347Arg	missense_variant	35/119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.4039G>C	p.Gly1347Arg	missense_variant	34/118	1		ENSP00000332371.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251024 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461708 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 21, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1347 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16484981, 18565177). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant disrupts the triple helix domain of COL7A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and variants at these glycine residues in COL7A1 are more frequently observed in individuals with disease than in the general population (PMID: 22058051). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL7A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17434). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 9804332, 12485454). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121912833, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1347 of the COL7A1 protein (p.Gly1347Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Aug 01, 2023	PP4, PP3, PM5, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2022	Located in the highly conserved Gly-X-Y repeat of the collagenous domain; Glycine substitution variants in this region of the COLVII protein destabilize the collagen triple helix resulting in skin fragility due to poor anchoring of the basement membrane to the underlying dermis (Pfendner and Lucky, 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12485454, 21448560, 25525159, 10504458, 16271705, 31670143, 26707537, 9804332, 20301481, 24077912) -

Epidermolysis bullosa dystrophica Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 26, 2020

- -

Epidermolysis bullosa dystrophica, autosomal recessive, localisata variant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.94		Loss of glycosylation at K1346 (P = 0.0033);
MVP		0.94
MPC		0.30
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.94
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912833; hg19: chr3-48622175;